A Trial of TTI-621 for Patients With Hematologic Malignancies and Selected Solid Tumors

Overview

About this study

Multicenter, open-label, phase 1a/1b trial of TTI-621 in subjects with relapsed or refractory hematologic malignancies and selected solid tumors.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

Phase 1a Escalation (Completed and now Closed)

  • Histologically documented, advanced lymphoma after the failure of at least 2 prior therapies with at least one site of measurable disease (≥ 1.5 cm in the long axis or ≥ 1.0 cm in both the long and short axis). Additionally, subjects with NHL (indolent and aggressive B-cell lymphomas) should have failed CD20-targeted therapy.
  • Adequate hematologic status (in the absence of transfusion and growth factor support for at least 28 days), defined as:
    • absolute neutrophil count (ANC) ≥ 1.5 x 109/L;
    • platelets ≥ 75 x 109/L;
    • hemoglobin ≥ 10 g/dL.

Phase 1b Expansion (Selected Cohorts Currently Open for Parts 2 and 3)

  • Advanced measurable malignancy documented by histology, cytology, flow cytometry, fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR) methodology in one of the following categories:
    • (closed) Small cell lung cancer (SCLC) (measurable disease by the Response Evaluation Criteria in Solid Tumors [RECIST], Version 1.1).
    • Histologically documented, advanced lymphoma after the failure of at least 2 prior systemic therapies with at least one site of measurable disease (≥ 1.5 cm in the long axis or ≥ 1.0 cm in both the long and short axis). Additionally, subjects with CD20-positive NHL (indolent and aggressive B-cell lymphomas) should have failed CD20-targeted therapy:
      • Indolent B-cell lymphoma;
      • Aggressive B-cell lymphoma;
      • Classic Hodgkin lymphoma.
        • Patients with cHL should have failed at least one checkpoint inhibitor therapy before enrolling to the nivolumab combination cohort. 
      • Peripheral T-cell lymphoma ([PTCL] as defined by mature T- and NK-cell neoplasms per WHO and CTCL), having failed at least 1 prior systemic therapy. Subjects with PTCL must have at least 1 site of measurable disease (≥ 1.5 cm in the long axis or ≥ 1.0 cm in both the long and short axis).
      • CTCL (both MF and SS):
        • Failed at least 2 prior systemic therapies for CTCL. Systemic therapy does not include local radiation therapy or topical agents;
        • Malignancy is measurable per global CTCL criteria (Olsen, 2011);
        • History of histologically-documented diagnosis of CTCL stage IIB to IVB (Olsen, 2011).
      • (closed) B-cell or T-cell acute lymphoblastic leukemia (ALL):
        • First or greater bone marrow relapse from complete remission; or
        • Any bone marrow relapse after allogeneic transplant; or
        • Absence of complete remission after 2 induction attempts employing standard regimens; or
        • Ph+ B-ALL if subjects are intolerant to or ineligible to receive tyrosine kinase inhibitor therapy or have progressed after at least one line of this therapy.
      • (closed) CLL: subjects should have failed at least 2 prior therapies, including CD20-targeted therapy.
      • (closed) Multiple myeloma (MM): subjects should have failed at least 3 prior therapies, including an immunomodulatory drug (IMID) and proteasome inhibitor-based therapy and have measurable disease as defined as 1 or more of the following:
        • serum M-protein > 0.5g/dl; and/or
        • urine M-protein > 200 mg/24 hours; and/or
        • in subjects who do not meet these criteria, serum free light chains (FLC) > 100 mg/L (involved light chain) and abnormal ratio (FLC kappa/FLC lambda);
        • biopsy-proven plasmacytoma.
      • (closed) AML, with the exception of AML M3 using the French American British (FAB) classification (i.e., acute promyelocytic leukemia [APL]).
      • (closed) MDS of WHO classifications RAEB-1 (refractory anemia with excess blasts) and RAEB-2.
      • (closed) BCR/ABL1-negative myeloproliferative neoplasm (MPN) or myeloproliferative/myelodysplastic overlap neoplasm (MPN/MDS) per the revised 2016 WHO criteria, including:
        • chronic phase (CP) (defined as peripheral blood and bone marrow <10% blasts) primary myelofibrosis or post-essential;
          • if the diagnosis is Myelofibrosis-CP, must have Dynamic International Prognostic Scoring System (DIPSS) intermediate-2/high risk disease (Passamonti et al., 2010) and either be: 1) intolerant/resistant to ruxolitinib or 2) ineligible for ruxolitinib therapy, as determined by the treating Investigator.
        • accelerated phase/blast phase MPN (MPN-AP/BP) (defined as either a peripheral blood or bone marrow with ≥10% blasts);
          • if the diagnosis is MPN-AP/BP, must have progressive/resistant disease after treatment with a DNA methyl transferase 1 (DNMT1) inhibitor therapy (e.g. azacitidine or decitabine), as determined by the treating Investigator.
        • chronic myelomonocytic leukemia (CMML) -1 or 2 characterized by:
          • > 1x109/L monocytes and 2-19% blasts in peripheral blood or Auer rods; and
          • dysplasia in ≥1hematopoietic line and 5-19% marrow blasts or Auer rods.
        • (closed) Subjects with MPN or MPN/MDS must not be eligible to proceed with hematopoietic stem cell transplantation (HSCT) and must have:
          • for MPN, an indication to treat with cytoreductive drugs (e.g. hydroxyurea, anagrelide, interferon, ruxolutinib, etc.), according to the judgment of the treating physician;
          • for MPN, documentation of inadequate response or intolerance to first line therapy, which includes at least one cytoreductive drug (e.g. hydroxyurea, anagrelide, interferon, ruxolutinib, etc.);
          • for CMML, documentation of inadequate response or intolerance to first line therapy, which includes at least one hypomethylating agent.
  • Hematologic status as follows (transfusions not permissible to achieve these levels within 14 days prior to the first dosing of study drug):
    • o ANC ≥1 x 109/L (not applicable to subjects with AML, ALL, MDS, or MPN/MDS);
    • o platelets ≥75 x 109/L (≥0 x 109/L if the patient has bone marrow involvement);
    • o hemoglobin ≥9 g/dL.

Phase 1b Expansion (Dose Optimization Part 4)

  • Histologically confirmed diagnosis of CTCL (both Mycosis Fungoides and Sezary Syndrome):
    • Failed at least 2 prior systemic therapies for CTCL (systemic therapy does not include local radiation therapy or topical agents);
    • Malignancy is measurable per global CTCL criteria (Olsen, 2011);
    • History of histologically-documented diagnosis of CTCL stage IB to IVB (Olsen, 2011).
  • Hematologic status as follows (transfusions not permissible to achieve these levels within 14 days prior to the first dosing of study drug):
    • ANC ≥ 1 x 109/L;
    • platelets ≥ 75 x 109/L;
    • hemoglobin ≥ 9 g/dL.

Both Phases

  • Male or female 18 years of age or older.
  • Availability of fresh or archived tumor tissue for immunohistochemical studies. Archival tissue may be used provided it was obtained subsequent to the last prior anti-cancer therapy. For subjects with SS, peripheral blood is acceptable.
  • Relapsed or refractory disease that has previously progressed on, or is currently progressing on standard anticancer therapy or for whom no other approved conventional therapy exists.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • Adequate coagulation function, defined as:
    • International Normalized Ratio (INR) < 1.5 x the upper limit of normal (ULN) for that laboratory;
    • partial thromboplastin time < 1.5 x ULN;
    • subjects receiving anticoagulation therapy must be on a stable dose with monitoring studies within therapeutic range per local institutional standards
  • Adequate hepatic function, defined as:
    • total bilirubin < 1.5 x ULN unless considered due to Gilbert’s disease;
    • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 1.5 x ULN or < 3 x ULN with documented liver metastases.
  • Adequate renal function, defined as estimated serum creatinine clearance > 30 mL/minute calculated using the Cockcroft-Gault equation.
  • Recovery from the toxicities of previous anticancer drugs or radiotherapy to Grade 0 or 1 (or to baseline grade if condition was pre-existing).
  • Commitment from male and female subjects of reproductive potential to use, from the time of screening through 60 days after the last dose of TTI-621, either:
    • one highly effective method of contraception, including hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants), intrauterine device (IUD) or intrauterine system (IUS), vasectomy, or tubal ligation; OR
    • at least 2 effective methods of contraception, including male condom, female condom, cervical cap, diaphragm, or contraceptive sponge; OR
    • abstain from sex during study participation and for 60 days after the last dose of TTI-621.

Exclusion Criteria:

Both Phases

  • (AML cohort closed) AML M3 by FAB classification (APL).
  • Known, current central nervous system disease involvement or untreated brain metastases.
  • Investigational agent or any anticancer drug within 14 days prior to planned start of treatment (with the exception of hydroxyurea in subjects with MPN, MPN/MDS, ALL or AML).
  • Allogeneic transplant within 30 days prior to the planned start of treatment or subjects with active graft-vs-host disease with the exception of Grade 1 skin involvement.
  • Prior anti-CD47 therapy, with the exception of prior TTI-621 therapy delivered intratumorally only.
  • Major surgery within 28 days prior to planned start of treatment.
  • Use of irreversible antiplatelet/anticoagulant agents within 7 days prior to planned start of treatment (except subjects with thrombocytosis where low dose aspirin is being used to reduce the risk of thrombosis); use of low dose aspirin (≤81 mg/day) and selected, reversible anticoagulants are permitted (low molecular weight heparin, heparin, warfarin and dabigatran).
  • History of hemolytic anemia or bleeding diathesis.
  • Uncontrolled infection requiring systemic antibiotics/antivirals/antifungals.
  • Chronic use of systemic corticosteroids of more than 20 mg per day of prednisone or equivalent; enrollment of post-transplant subjects who are on corticosteroids for graft-vs-host disease prophylaxis requires approval of the Medical Monitor. CTCL patients who are on a stable dose of medium or low potency topical corticosteroids for at least 4 weeks prior to study entry may continue its use on study at the same dose.
  • Known hypersensitivity to any component of study drug.
  • Positive serum pregnancy test in females of child-bearing potential or current breastfeeding.
  • Significant cardiovascular disease such as symptomatic congestive heart failure (New York Heart Association Class III or IV), symptomatic coronary artery disease, myocardial infarction within the last 6 months, unstable arrhythmia requiring treatment, unstable angina, or prolonged QTc interval > 480 milliseconds (Grade 2 or higher) (QTc interval calculation at the discretion of the Investigator).
  • Active hepatitis B or C or a history of HIV infection.
  • Other significant medical condition unrelated to the primary malignancy that would compromise subject’s safety or ability to comply with protocol requirements.
  • Inability for the subject to complete protocol requirements, such as geographic considerations, psychiatric disorders, or other compliance concerns.
  • Prior Grade 4 rituximab infusion-related reaction (rituximab combination arm only).
  • Active autoimmune disease or history of autoimmune disease that might recur (nivolumab combination arm only); subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Stephen Ansell, M.D., Ph.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

James Foran, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available
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CLS-20200922

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